Infection by the human immunodeficiency virus (HIV) severely impacts the human immune system. With the advent of highly active antiretroviral therapy (HAART), the lives of HIV infected individuals have much improved. However, immune impairment still persists. While AIDS-related malignancies have decreased significantly, the occurrence of non-AIDS related cancers is higher in HIV infected individuals versus the general population. The reasons for this phenomenon are still under investigation. However, studies have implicated the loss of CD4 T cells and the chronic immune activation observed in HIV patients as potential factors that can impact the function and maturation of cytotoxic T cells (CTL), the effector arm of our immune system. Such outcome will, in turn, influence the ability of the host to mount effective immune responses against other pathogens and cancers. In this proposal, we aim to examine the impact of HIV infection on the responses elicited by tumor specific CTLs. We have constructed a modified version of the BLT humanized mouse model where we generated functional melanoma specific CD8 T cells from genetically engineered human progenitors. These mice will be infected with HIV and then challenged with melanoma tumors to assess the quality of anti-melanoma immune responses. In Specific Aim #1, we propose to in vivo monitor tumor regression and transgenic CTL maturation in the context of HIV infection. Furthermore, we will isolate the melanoma specific CTL and further examine their functionality. In Specific Aim #2, we will determine if the administration of HAART remedies the observed defects caused by HIV infection. In both aims, collected immune monitoring data will be further analyzed to further characterize the impact of HIV infection on the transgenic CTL. Finally, for both aims, transgenic CTLs will be isolated and used for microarray analysis to study any gene expression changes due to HIV infection. The proposed studies will expand our knowledge on the function of CTLs within the context of HIV infection. Such knowledge is essential, as it will pave the way for the development of improved immune based interventions for HIV infected individuals.